Affinage

LRP4

Low-density lipoprotein receptor-related protein 4 · UniProt O75096

Length
1905 aa
Mass
212.0 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRP4 is a multifunctional LDL receptor-related transmembrane protein that operates as a ligand-binding hub coordinating distinct signaling programs at the neuromuscular junction, in bone, and in the CNS (PMID:18848351, PMID:21471202, PMID:27294513). At the neuromuscular junction it serves as the obligate coreceptor for neural agrin: agrin binds the N-terminal LDLa repeats and β-propeller domains of LRP4, promoting LRP4 association with the first Ig-like domain of MuSK and activating MuSK kinase to drive AChR clustering and postsynaptic differentiation (PMID:18848351, PMID:18957220, PMID:21969364). Structural work resolved this assembly first as an agrin–LRP4 tetramer dependent on the neuronal agrin z8 loop and ultimately as a 1:1:1 agrin/LRP4/MuSK ternary complex in which arc-shaped LRP4 captures both ligands in a central cavity to promote a direct agrin–MuSK interaction (PMID:22302937, PMID:37252960). LRP4's extracellular region is sufficient for this signaling, with the intracellular domain dispensable for synapse formation (PMID:22038977), and the receptor is additionally required for NMJ maintenance and stabilization of synaptic agrin (PMID:25319686). Beyond MuSK activation, muscle-derived LRP4 acts as a retrograde signal that binds motor axons to organize presynaptic differentiation independently of MuSK (PMID:22854782, PMID:22794264). In bone, LRP4 is an osteoblast/osteocyte receptor that binds sclerostin and facilitates its inhibition of Wnt/β-catenin signaling through its extracellular β-propeller, anchoring sclerostin in bone; loss or mutation of this function elevates circulating sclerostin and produces high bone mass (PMID:21471202, PMID:19936252, PMID:25404300, PMID:26751728, PMID:31585407). LRP4 more broadly antagonizes canonical Wnt signaling during limb, tooth, and chondrocyte development (PMID:19116665, PMID:20381006, PMID:16207730, PMID:25091481). In the CNS, astrocytic LRP4 suppresses ATP/adenosine release to control glutamatergic transmission and ischemic injury, while neuronal LRP4 governs synapse number, dendritic development, hippocampal plasticity, and adult neurogenesis (PMID:27294513, PMID:25407677, PMID:29061639, PMID:29212737, PMID:31268420). Recessive LRP4 mutations cause Cenani–Lenz syndrome by abolishing Wnt antagonism, and β-propeller mutations cause congenital myasthenic syndrome by reducing agrin/MuSK binding (PMID:20381006, PMID:24234652). Anti-LRP4 autoantibodies targeting the β3 domain disrupt agrin-enhanced LRP4–MuSK interaction and are pathogenic in myasthenia (PMID:34233932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    Established the molecular identity of the long-sought agrin receptor, resolving how a secreted neural signal triggers postsynaptic assembly.

    Evidence Biochemical binding, co-IP, RNAi, and AChR clustering assays in myotubes identifying LRP4 as the agrin coreceptor that forms an agrin-stimulated complex with MuSK

    PMID:18848351 PMID:18957220

    Open questions at the time
    • Did not resolve domain architecture of the binding interfaces
    • Stoichiometry and structural basis of MuSK activation unknown
  2. 2011 High

    Mapped the agrin-binding region and defined LRP4 as a cis-acting MuSK ligand with agrin as allosteric regulator, explaining the mechanics of complex assembly.

    Evidence Deletion mutagenesis, co-IP, kinase activity and surface binding assays localizing agrin binding to LDLa repeats and the first β-propeller

    PMID:21969364

    Open questions at the time
    • No atomic structure of the interface yet
    • How the intracellular domain contributes was unresolved
  3. 2012 High

    Provided the first structural picture of agrin–LRP4 recognition, showing tetramerization is essential for AChR clustering.

    Evidence X-ray crystallography of the agrin–LRP4 complex with structure-guided mutagenesis and AChR clustering assays

    PMID:22302937

    Open questions at the time
    • Did not include MuSK in the structure
    • Mechanism by which tetramer activates MuSK kinase not defined
  4. 2012 High

    Revealed a MuSK-independent function of LRP4 as a retrograde organizer of presynaptic differentiation, expanding its role beyond postsynaptic signaling.

    Evidence Conditional knockouts, axon binding assays, co-culture synaptogenesis, and synaptic protein clustering analyses in vivo

    PMID:22794264 PMID:22854782

    Open questions at the time
    • Presynaptic receptor for LRP4 on motor axons not identified
    • Signal transduction in the nerve terminal unknown
  5. 2011 High

    Defined LRP4 as a facilitator of sclerostin's Wnt inhibition in bone and linked this to high-bone-mass disease mutations.

    Evidence TAP proteomics, recombinant binding, RNAi, bone mineralization assays, and analysis of R1170W/W1186S overgrowth mutations

    PMID:21471202

    Open questions at the time
    • In vivo confirmation of facilitator role at the time limited
    • Relationship to LRP5/6 receptor complex unresolved
  6. 2014 High

    Genetically established LRP4 as the osteoblast-lineage receptor anchoring sclerostin and demonstrated loss raises circulating sclerostin while abolishing its Wnt inhibition.

    Evidence Osteoblast/osteocyte conditional knockouts with histomorphometry, serum sclerostin ELISA, Wnt reporters, and RANKL/OPG measurements

    PMID:25404300 PMID:31585407

    Open questions at the time
    • Quantitative contribution of LRP4 vs LRP5/6 to sclerostin action not fully partitioned
  7. 2015 High

    Uncovered a sclerostin-independent osteoblastic pathway in which LRP4 controls ATP/adenosine-A2AR signaling to regulate osteoclastogenesis, shared with astrocytes.

    Evidence Conditional knockouts, ATP/adenosine measurements, and genetic/pharmacological A2AR inhibition in osteoclast differentiation assays

    PMID:25733894 PMID:28193701

    Open questions at the time
    • Mechanism by which LRP4 stabilizes the prorenin receptor not detailed
    • Cross-tissue generality of the ATP pathway not exhaustively tested
  8. 2016 High

    Linked astrocytic LRP4 to control of glutamatergic transmission via suppression of ATP/adenosine release, establishing a glial role in synaptic regulation.

    Evidence Astrocyte-specific conditional knockout with electrophysiology, gliotransmitter measurements, and adenosine A1 receptor pharmacological rescue

    PMID:27294513

    Open questions at the time
    • Molecular mechanism coupling LRP4 to ATP release machinery not fully defined
  9. 2010 High

    Showed LRP4 acts as a negative regulator of canonical Wnt signaling underlying limb and developmental patterning, with human disease validation.

    Evidence Knockout mice, in situ hybridization, Wnt reporter assays, and Cenani–Lenz syndrome mutation analysis across families

    PMID:16207730 PMID:19116665 PMID:20381006

    Open questions at the time
    • Precise biochemical mechanism of Wnt antagonism (LRP6 sequestration vs ligand competition) not fully resolved
  10. 2014 High

    Isolated a brain-autonomous role for LRP4 in hippocampal plasticity and cognition using a muscle-rescue strategy.

    Evidence Muscle-rescued Lrp4 mutant mice with electrophysiology, spine density quantification, LTP, and behavioral testing

    PMID:25407677 PMID:28606304 PMID:29061639

    Open questions at the time
    • Receptor partners mediating CNS synaptic effects only partly identified
    • SRPK79D pathway connection drawn from Drosophila
  11. 2023 High

    Resolved the complete ternary signaling complex, defining at atomic resolution how LRP4 simultaneously recruits agrin and MuSK to trigger receptor activation.

    Evidence Cryo-EM structure of the extracellular agrin/LRP4/MuSK complex at 1:1:1 stoichiometry

    PMID:37252960

    Open questions at the time
    • Conformational dynamics of activation in the membrane context not captured
    • How tetrameric and 1:1:1 models reconcile not addressed
  12. 2018 High

    Identified LRP4 stability control via sarcoglycan-α and ubiquitination as a determinant of age-related NMJ decline.

    Evidence Co-IP, ubiquitination assays, and AAV9-mediated SGα rescue with electrophysiology in aged mice

    PMID:24140340 PMID:30171091

    Open questions at the time
    • E3 ligase mediating LRP4 ubiquitination not identified
  13. 2023 High

    Extended LRP4 function to proprioception, showing it is required for muscle spindle formation through Egr3 and trans interactions with APP/APLP2.

    Evidence Conditional and inducible knockouts, immunostaining, proprioception testing, and co-IP of LRP4 with APP/APLP2

    PMID:23986861 PMID:36765071

    Open questions at the time
    • Mechanistic link between LRP4 and Egr3 expression unresolved
    • Functional consequence of APP/APLP2 trans-interaction not fully defined
  14. 2022 Medium

    Expanded the LRP4 ligand/partner repertoire into vascular and metabolic contexts via VWF/integrin and sclerostin-responsive adipocyte signaling.

    Evidence siRNA, proximity ligation, co-IP, carotid ligation model (VWF/αVβ3); cell-specific knockouts with metabolic phenotyping (adipocyte sclerostin cascade)

    PMID:30842262 PMID:33576766

    Open questions at the time
    • VWF–LRP4 interaction in VSMC from single lab, not independently replicated
    • Mechanism integrating LRP4 with αVβ3 signaling incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LRP4's distinct ligand-binding modules are spatially and temporally partitioned across tissues to select among MuSK activation, sclerostin facilitation, Wnt antagonism, and ATP-pathway control remains unresolved.
  • No unified model linking domain occupancy to downstream pathway choice
  • Intracellular signaling outputs of LRP4 in non-muscle tissues largely uncharacterized
  • Regulated proteolysis and the role of released ectodomain across tissues incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0001618 virus receptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005654 nucleoplasm 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
AGRNAPLP2APPDLG4MESDMUSKRYR2SOST
Complex memberships
agrin/LRP4/MuSK ternary complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Lrp4 is a direct receptor for Agrin and forms a complex with MuSK, mediating MuSK activation by Agrin at the neuromuscular junction. Biochemical binding assays, co-immunoprecipitation, functional cell-based assays Cell High 18848351
2008 LRP4 is expressed specifically in myotubes, binds neuronal agrin, enables agrin binding and MuSK signaling in non-responsive cells, forms an agrin-stimulated complex with MuSK, and becomes tyrosine-phosphorylated upon agrin stimulation, establishing it as a coreceptor for agrin required for MuSK signaling and AChR clustering. Co-immunoprecipitation, RNAi knockdown, tyrosine phosphorylation assays, AChR clustering assay in C2C12 myotubes Neuron High 18957220
2011 Agrin binds to the N-terminal region of Lrp4 (including LDLa repeats and first β-propeller domain), which promotes association between Lrp4 and the first Ig-like domain of MuSK and stimulates MuSK kinase activity; Lrp4 acts as a cis-acting ligand for MuSK while Agrin functions as an allosteric paracrine regulator. Deletion mutagenesis, co-immunoprecipitation, kinase activity assays, surface binding assays on myotubes The Journal of biological chemistry High 21969364
2012 Crystal structure of the agrin-LRP4 complex reveals two agrin-LRP4 heterodimers forming a tetramer; the neuronal agrin z8 loop promotes tetrameric complex formation through two additional interfaces, and this tetrameric assembly is essential for neuronal agrin-induced AChR clustering. X-ray crystallography, structure-guided mutagenesis, AChR clustering assay Genes & development High 22302937
2023 Cryo-EM structure of the extracellular ternary agrin/LRP4/MuSK complex (1:1:1 stoichiometry) shows that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, promoting a direct interaction between agrin and MuSK and revealing the mechanism of MuSK receptor activation. Cryo-EM structural determination Proceedings of the National Academy of Sciences of the United States of America High 37252960
2012 Lrp4 functions as a direct muscle-derived retrograde signal for presynaptic differentiation, independent of MuSK activation; Lrp4 binds to motor axons and induces clustering of synaptic-vesicle and active-zone proteins. Conditional genetic knockout, in vivo neuromuscular junction analysis, axon binding assays, synaptic protein clustering assays Nature High 22854782
2012 Muscle-specific LRP4 mutation reveals roles in determining AChR cluster positioning, postsynaptic differentiation, and axon terminal development; LRP4 in motoneurons can also induce AChR clusters in trans, and LRP4 expressed in HEK293 cells increases synapsin/SV2 puncta in contacting axons of co-cultured neurons. Cell-type-specific conditional knockout, co-culture synaptogenesis assay, double-mutant epistasis analysis Neuron High 22794264
2011 LRP4 facilitates the inhibitory action of sclerostin on Wnt1/β-catenin signaling; the extracellular β-propeller domain of LRP4 is required for this facilitator activity; two bone overgrowth mutations (R1170W and W1186S) impair LRP4-sclerostin interaction and LRP4 sclerostin-facilitator function. Tandem affinity purification proteomics, recombinant protein binding assays, RNAi knockdown, overexpression, in vitro bone mineralization assay, mutation analysis The Journal of biological chemistry High 21471202
2014 Conditional deletion of LRP4 in adult muscle leads to fragmented AChR clusters, reduced junctional folds, impaired neuromuscular transmission, loss of synaptic agrin and its 90 kDa fragments (preceding loss of other synaptic components), demonstrating LRP4 is required for NMJ maintenance and may regulate synaptic agrin stability. Inducible muscle-specific knockout (doxycycline-driven), electrophysiology (CMAP, mEPP), electron microscopy, immunostaining, Western blot The Journal of neuroscience High 25319686
2009 Lrp4 binds Dkk1 and sclerostin in vitro and is expressed in osteoblasts; Lrp4-deficient mice show reduced bone mineral content/density and altered bone turnover markers, establishing Lrp4 as an osteoblast-expressed receptor for Dkk1 and sclerostin with a physiological role in bone growth and turnover. In vitro protein binding assays, micro-CT analysis, serum/urinary bone turnover marker measurements in knockout mice PloS one High 19936252
2008 Lrp4 modulates and integrates BMP and canonical Wnt signaling during tooth morphogenesis by binding the secreted BMP antagonist Wise; Wise secreted from mesenchyme binds LRP4 on epithelial cells to modulate Wnt activity, with downstream mediation by Shh signaling. Mouse genetic knockout, phenotypic analysis, signaling pathway analysis (BMP/Wnt/Shh markers) PloS one High 19116665
2010 Recessive LRP4 mutations in Cenani-Lenz syndrome patients abolish LRP4's ability to antagonize LRP6-mediated activation of canonical Wnt signaling, establishing LRP4 as a negative regulator of Wnt/β-catenin signaling in limb development. Homozygosity mapping, gene sequencing, Wnt signaling reporter assays with mutant constructs American journal of human genetics High 20381006
2016 Astrocytic Lrp4 regulates glutamate release by suppressing ATP release from astrocytes; loss of astrocytic Lrp4 enhances ATP release, elevates hippocampal adenosine, and impairs glutamatergic transmission and synaptic release probability; these deficits are rescued by adenosine A1 receptor blockade; Lrp4 responds to agrin in this pathway. Astrocyte-specific conditional knockout, electrophysiology, ATP/adenosine measurements, pharmacological rescue Nature neuroscience High 27294513
2006 Megf7/Lrp4 is required for normal apical ectodermal ridge (AER) formation; its absence causes ectopic expression of Fgf8, Shh, Bmp2, Bmp4, and Wnt7a, and reduced apoptosis leading to polysyndactyly; Megf7 can antagonize canonical Wnt signaling in vitro. Gene targeting (knockout mice), in situ hybridization, immunostaining, in vitro Wnt signaling assays Human molecular genetics High 16207730
2013 MuSK IgG4 autoantibodies bind to the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation, but do not directly affect MuSK dimerization or MuSK internalization. Co-immunoprecipitation, epitope mapping, MuSK phosphorylation assays, passive transfer mouse model Proceedings of the National Academy of Sciences of the United States of America High 24297891
2011 The extracellular region of Lrp4 is sufficient for Agrin-stimulated MuSK phosphorylation and AChR clustering; the intracellular region is dispensable, and a Lrp4-CD4 chimera lacking the Lrp4 intracellular domain rescues neuromuscular synapse formation and neonatal lethality in Lrp4 mutant mice. Domain-swap chimeric receptor rescue experiment in Lrp4 mutant mice, AChR clustering assays in myotubes Developmental dynamics High 22038977
2014 Loss of Lrp4 in osteoblast-lineage cells increases bone formation and reduces osteoclastogenesis; sclerostin serum levels rise but its inhibition of Wnt/β-catenin signaling and osteoblast differentiation is abolished; sclerostin-induced RANKL upregulation is impaired, lowering RANKL/OPG ratio. This establishes LRP4 as a receptor for sclerostin to inhibit Wnt/β-catenin signaling in bone, with Lrp4 deficiency in bone causing elevated circulating sclerostin. Osteoblast/osteocyte-specific conditional knockout, bone histomorphometry, serum sclerostin ELISA, Wnt reporter assays, RANKL/OPG measurements Proceedings of the National Academy of Sciences of the United States of America High 25404300
2015 Lrp4 in osteoblast-lineage cells promotes osteoclastogenesis; loss of Lrp4 stabilizes the prorenin receptor (PRR) and increases PRR/V-ATPase-driven ATP release, enhancing adenosine production and A2AR signaling, which reduces RANK-mediated osteoclastogenesis. Pharmacological and genetic inhibition of A2AR restores osteoclastogenesis and reduces trabecular bone mass. Osteoblast-specific conditional knockout, ATP/adenosine measurements, pharmacological and genetic inhibition of A2AR, osteoclast differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 25733894
2006 LRP4 interacts with postsynaptic scaffold proteins PSD-95 and SAP97 via its C-terminal PDZ domain-binding motif; CaMKII phosphorylates the C-terminal cytoplasmic region at Ser1887 and Ser1900, and phosphorylation at Ser1900 suppresses interaction with PSD-95 and SAP97; LRP4 is concentrated in synaptic fractions and associates with NMDA receptor subunits. Co-immunoprecipitation, subcellular fractionation, in vitro CaMKII phosphorylation assay, site-directed mutagenesis, immunocytochemistry The European journal of neuroscience High 16819975
2013 APP interacts directly with LRP4; agrin binds APP and cooperatively enhances the APP-LRP4 interaction; APP synergistically increases agrin-induced AChR clustering in myotubes; deletion of LRP4 transmembrane domain markedly enhanced by APP loss causes perinatal lethality with severely reduced NMJ size and number. Co-immunoprecipitation, pull-down, AChR clustering assay, double-mutant mouse genetic analysis eLife High 23986861
2013 LRP4 mutations in the third β-propeller domain (p.Glu1233Lys and p.Arg1277His) decrease binding affinity for both MuSK and agrin, causing congenital myasthenic syndrome; position-specific analysis reveals the edge of the third β-propeller regulates MuSK signaling while its central cavity governs Wnt signaling. Exome sequencing, binding affinity assays, Wnt reporter assays, naturally occurring and engineered mutation analysis Human molecular genetics High 24234652
2019 Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2) in hippocampal neural stem/progenitor cells; Lrp4 mutation blocks basal and enriched environment-induced NSPC proliferation and newborn neuron maturation; this identifies an Agrin-Lrp4-Ror2 signaling axis for adult neurogenesis. Co-immunoprecipitation, conditional genetic knockout, BrdU/EdU proliferation assays, adult hippocampal neurogenesis quantification eLife High 31268420
2013 Connective tissue growth factor (CTGF/CCN2) directly binds to the third β-propeller domain of LRP4, enhances LRP4-MuSK binding, facilitates LRP4 plasma membrane localization, and enhances agrin-induced MuSK phosphorylation and AChR clustering; Ctgf-deficient mice have small AChR clusters, reduced presynaptic active zones, and impaired NMJ transmission. Co-immunoprecipitation, direct protein binding assays, cell-surface expression assays, MuSK phosphorylation assay, AChR clustering, Ctgf knockout mouse NMJ analysis, electrophysiology EMBO reports High 32558157
2020 Astrocytic LRP4 promotes Aβ uptake, likely by interacting with ApoE; genetic deletion of Lrp4 augments Aβ plaques in 5xFAD mice and exacerbates deficits in neurotransmission, hippocampus-PFC synchrony, and cognition. Astrocyte-specific conditional knockout, co-immunoprecipitation (LRP4-ApoE), Aβ plaque quantification, electrophysiology, cognitive testing in 5xFAD model The Journal of neuroscience Medium 32457076
2016 Anti-LRP4 autoantibodies from a sclerosteosis patient with R1170Q LRP4 mutation impair sclerostin inhibition of Wnt signaling; Cenani-Lenz mutations impair LRP4 membrane trafficking (in contrast to sclerosteosis mutations that impair sclerostin binding); loss of sclerostin binding to mutated LRP4 dramatically increases circulating sclerostin, establishing LRP4 as the anchor retaining sclerostin in bone. Wnt reporter assays, membrane trafficking assays, serum sclerostin measurement in patient, mutation functional analysis Journal of bone and mineral research High 26751728
2014 Lrp4 is required for hippocampal synaptic plasticity; Lrp4-deficient mice (rescued in muscle) show reduced frequency of spontaneous release events, reduced spine density on primary apical dendrites, impaired CA3-CA1 LTP, and profound cognitive deficits. Muscle-rescue genetic mouse model, electrophysiology, spine density quantification, behavioral cognitive testing eLife High 25407677
2018 Sarcoglycan α (SGα) interacts with LRP4 and delays LRP4 degradation; LRP4 ubiquitination is augmented in aged muscles; AAV9-mediated SGα expression in muscles mitigates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, identifying a mechanism for age-related NMJ decline through LRP4 stability. Co-immunoprecipitation (LRP4-SGα), ubiquitination assay, AAV9-mediated transgene delivery, AChR cluster analysis, electrophysiology in aged mice The Journal of neuroscience High 30171091
2017 In Drosophila, presynaptic LRP4 functions via the conserved kinase SRPK79D to ensure normal excitatory synapse number and behavior; loss of presynaptic LRP4 reduces excitatory synapse number, impairs active zone architecture, and abolishes olfactory attraction, which can be suppressed by reducing presynaptic GABAB receptors. Genetic loss-of-function, genetic epistasis with SRPK79D and GABAB receptors, synaptic morphology analysis, behavioral assays eLife High 28606304
2017 Neuronal (cortical/hippocampal) LRP4 is required for synapse density and dendritic development; LRP4 knockdown reduces synapse density and primary dendrite number, while overexpression increases spines and dendrite number; transsynaptic tracing shows fewer presynaptic neurons contact LRP4-knockdown neurons. LRP4 miRNA knockdown/overexpression in cultured neurons and in utero electroporation, spine density quantification, rabies virus transsynaptic tracing Development (Cambridge, England) High 29061639
2013 Prepatterning of AChR clusters in mice requires Lrp4 but not the MuSK Fz-like domain; in zebrafish, prepatterning requires the MuSK Fz-like domain but not Lrp4; neuromuscular synapse formation in both species requires Lrp4, MuSK, and neuronal Agrin. Genetic knockout and rescue experiments in mice and zebrafish, comparative epistasis analysis Genes & development High 27151977
2013 Mesdc2 (a chaperone) binds to intracellular Lrp4, promotes its glycosylation and cell-surface expression; Mesdc2 knockdown suppresses Lrp4 surface expression, MuSK activation, and postsynaptic specialization in muscle cells. Co-immunoprecipitation, glycosylation assay, cell-surface expression assay, RNAi knockdown, AChR clustering assay FEBS letters Medium 24140340
2017 Loss of Lrp4 in osteoblasts promotes osteoclastogenesis via increased PRR/V-ATPase-driven ATP release, enhanced adenosine-A2AR signaling, which reduces RANK-mediated osteoclastogenesis; this pathway is distinct from sclerostin-facilitation and also operates in astrocytes where Lrp4 regulates glutamatergic transmission through ATP/adenosine. Conditional knockout, ATP release measurement, pharmacological and genetic A2AR inhibition, osteoclast differentiation assays The Journal of cell biology High 28193701
2023 ColQ binds directly to LRP4 (not to MuSK directly); ColQ interacts indirectly with MuSK through LRP4; the N-terminal region of LRP4 containing the agrin-binding sites is also required for ColQ binding; agrin and ColQ compete for LRP4 binding; ColQ reduces MuSK phosphorylation levels but increases MuSK cell-surface accumulation in agrin-stimulated myotubes. Co-immunoprecipitation, pull-down, plate-binding assay, surface plasmon resonance, MuSK phosphorylation assay in myotubes The Journal of biological chemistry High 37356721
2010 Lrp4 undergoes regulated intramembranous processing through metalloproteases and gamma-secretase cleavage; the soluble extracellular domain negatively regulates Wnt signaling; expression of truncated Lrp4 alleles lacking transmembrane and intracellular domains (releasing ECD) is sufficient to confer viability, whereas null mutations are perinatal lethal. Gene targeting, in vitro metalloprotease/gamma-secretase inhibitor treatment, Wnt reporter assays with soluble ECD PloS one Medium 20383322
2007 ApoE co-immunoprecipitates with LRP4 from brain homogenate and from COS7 cells expressing LRP4; blocking the ligand-binding domain of LRP4 reduces neuronal viability and impairs synaptic structure in cultured cortical neurons, and suppresses apoE binding to LRP4, suggesting apoE is an endogenous ligand for LRP4. Co-immunoprecipitation, antibody blocking, neuronal viability assay, synaptic structure analysis Brain research Medium 17889837
2019 Lrp4 mediates bone homeostasis and mechanotransduction through sclerostin interaction in vivo; Lrp4 R1170W knockin mice have high bone mass, are less sensitive to altered sclerostin levels, and are protected from disuse-induced bone loss; Sost transgene overexpression has osteopenic effects in Lrp4-WT but not Lrp4KI mice. Knockin mouse model, bone densitometry, sclerostin transgene epistasis, disuse-induced bone wasting model iScience High 31585407
2022 Sclerostin binds LRP4 with stronger affinity than LRP6 (demonstrated by yeast display); LRP4 facilitates sclerostin binding to LRP6; a sclerostin mutant (SclN93A) that binds LRP4 but not LRP6 does not inhibit Wnt signaling alone but competes with sclerostin at LRP4 and antagonizes sclerostin inhibition of Wnt signaling in osteoblasts. Yeast display binding affinity measurements, Wnt reporter assays, competitive binding assay, subcutaneous injection in mice with bone formation readout Cellular and molecular life sciences High 35099616
2018 LRP4 regulates peripheral nerve regeneration through an axon-extrinsic mechanism independent of membrane anchoring and MuSK co-receptor signaling; lrp4 mutant zebrafish show normal pioneer axon regeneration but follower axons stall at the injury gap; Lrp4 coordinates realignment of denervated Schwann cells with regenerating axons. Live imaging in zebrafish, lrp4 genetic mutant analysis, domain-specific rescue with membrane-anchoring and MuSK-signaling deficient constructs Nature communications High 29921864
2020 Neuronal MT1-MMP cleaves Lrp4 (releasing its ectodomain) and facilitates agrin deposition and presynaptic differentiation; treatment with Lrp4 ectodomain rescues MMP-inhibitor-suppressed presynaptic differentiation; MT1-MMP knockdown inhibits nerve-induced AChR clustering and synaptic structures at Xenopus NMJs in vivo. MMP inhibitor treatment, MT1-MMP knockdown, exogenous Lrp4 ECD rescue, nerve-muscle co-culture AChR clustering assay, in vivo Xenopus NMJ analysis Journal of cell science Medium 32591486
2023 LRP4 is required for muscle spindle formation and maintenance; Lrp4 mutation disrupts sensory nerve terminals in muscle spindles; inducible adult KO impairs sensory synapses and movement coordination; LRP4 is critical for Egr3 expression during development; in adult mice LRP4 interacts in trans with APP and APLP2 on sensory terminals. Conditional and inducible knockout, immunostaining, proprioception behavioral testing, co-immunoprecipitation (LRP4-APP/APLP2 trans-interaction) Nature communications High 36765071
2021 Human anti-LRP4/agrin antibodies are pathogenic in mice; patient Ig inhibits agrin-elicited MuSK activation and AChR clustering; the antibodies recognize the β3 domain of LRP4 and reduce agrin-enhanced LRP4-MuSK interaction. Passive transfer of patient Ig to mice, muscle force measurement, electrophysiology, NMJ morphology, epitope mapping by domain binding assays Neurology High 34233932
2022 VWF binds to LRP4 on vascular smooth muscle cells via the VWF A2 domain; LRP4 co-localizes and co-immunoprecipitates with αVβ3 integrin; LRP4 mediates VWF-induced VSMC proliferation and migration downstream of αVβ3 signaling. siRNA knockdown of LRP4, proximity ligation assay, co-immunoprecipitation, confocal co-localization, domain-specific binding assay (VWF A2 domain), carotid ligation model in mice Cardiovascular research Medium 33576766
2017 Astrocytic Lrp4 contributes to ischemia-induced brain injury by regulating ATP release and adenosine-A2AR signaling; Lrp4 knockout in astrocytes increases ATP release, elevates adenosine, and reduces brain injury; pharmacological inhibition of A2AR or P2X7R signaling diminishes this protective effect. Astrocyte-specific conditional knockout, photothrombotic and tMCAO stroke models, gliotransmitter measurement (ATP, adenosine, glutamate), pharmacological inhibition of A2AR/P2X7R Stroke High 29212737
2015 LRP4 promotes extracellular matrix production (Col2a1, Acan, Col10a1, total proteoglycans) and chondrocyte differentiation by suppressing Wnt/β-catenin signaling in ATDC5 chondrocyte cells; LRP4 knockdown reduces Sox9 and Dkk1 expression; rescue with β-catenin/TCF inhibitor restores ECM production in LRP4-knockdown cells. LRP4 overexpression/lentiviral knockdown in ATDC5 cells, gene expression assays, proteoglycan quantification, Wnt reporter assay, pharmacological rescue with β-catenin/TCF inhibitor Biochemical and biophysical research communications Medium 25091481
2013 In Agrin/Lrp4 signaling in cartilage, agrin requires both LRP4 and α-dystroglycan as receptors; siRNA knockdown of LRP4 or blocking antibodies against α-dystroglycan inhibit agrin-driven chondrocyte differentiation and cartilage ECM formation; agrin is lost progressively in OA cartilage. siRNA knockdown of LRP4 and α-dystroglycan, blocking antibodies, 3D culture differentiation assays, in vivo ectopic cartilage formation assay Annals of the rheumatic diseases Medium 26290588
2019 Lrp4 expression in adipocytes responds to sclerostin signaling; AdΔLrp4 mice phenocopy sclerostin deficiency in whole-body metabolism with improved glucose/lipid homeostasis; epistasis studies place adipocyte Lrp4 and sclerostin in the same genetic cascade; ObΔLrp4 mice with dramatically elevated serum sclerostin accumulate body fat and develop glucose intolerance. Adipocyte- and osteoblast-specific conditional knockout, glucose/insulin tolerance tests, serum fatty acid measurements, genetic epistasis The Journal of biological chemistry High 30842262

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 541 18848351
2008 LRP4 serves as a coreceptor of agrin. Neuron 445 18957220
2011 Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. Journal of neurology 242 21814823
2013 A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. Journal of autoimmunity 232 24373505
2011 Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. The Journal of biological chemistry 224 21471202
2013 MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proceedings of the National Academy of Sciences of the United States of America 213 24297891
2009 Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PloS one 174 19936252
2008 Lrp4 modulates extracellular integration of cell signaling pathways in development. PloS one 164 19116665
2012 Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses. Nature 161 22854782
2012 Structural basis of agrin-LRP4-MuSK signaling. Genes & development 146 22302937
2012 Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron 138 22794264
2010 LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. American journal of human genetics 137 20381006
2013 MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. PloS one 129 24244707
2011 Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK). The Journal of biological chemistry 120 21969364
2014 LRP4 is critical for neuromuscular junction maintenance. The Journal of neuroscience : the official journal of the Society for Neuroscience 118 25319686
2005 Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Human molecular genetics 117 16207730
2013 LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Human molecular genetics 96 24234652
2014 Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proceedings of the National Academy of Sciences of the United States of America 93 25404300
2013 LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Annals of clinical and translational neurology 90 25356387
2016 Lrp4 in astrocytes modulates glutamatergic transmission. Nature neuroscience 89 27294513
2015 Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proceedings of the National Academy of Sciences of the United States of America 84 25733894
2020 Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle & nerve 68 32483837
2012 Structural mechanisms of the agrin-LRP4-MuSK signaling pathway in neuromuscular junction differentiation. Cellular and molecular life sciences : CMLS 67 23178848
2013 Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling. Development (Cambridge, England) 65 23293290
2006 Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse. Genomics 65 16517118
2016 A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 56 26751728
2013 APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. eLife 56 23986861
2015 Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Scientific reports 54 26355076
2018 Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 30171091
2017 Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons. eLife 53 28606304
2006 Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease. Genomics 51 16963222
2020 A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 32457076
2016 Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution. Genes & development 49 27151977
2015 Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo. Annals of the rheumatic diseases 49 26290588
2010 Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome. PloS one 49 20454682
2015 LRP4 in neuromuscular junction and bone development and diseases. Bone 48 26071838
2017 Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders. Expert opinion on therapeutic targets 47 28825343
2006 Interaction of LDL receptor-related protein 4 (LRP4) with postsynaptic scaffold proteins via its C-terminal PDZ domain-binding motif, and its regulation by Ca/calmodulin-dependent protein kinase II. The European journal of neuroscience 47 16819975
2019 Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin's endocrine effects on body composition and glucose metabolism. The Journal of biological chemistry 45 30842262
2019 Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice. eLife 45 31268420
2015 Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia. JAMA neurology 42 26052878
2014 Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4. eLife 42 25407677
2006 Identification of a doublet missense substitution in the bovine LRP4 gene as a candidate causal mutation for syndactyly in Holstein cattle. Genomics 42 16859890
2007 Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4). BMC genetics 41 17319939
2021 microRNA-136-5p from bone marrow mesenchymal stem cell-derived exosomes facilitates fracture healing by targeting LRP4 to activate the Wnt/β-catenin pathway. Bone & joint research 39 34847690
2017 Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development. Development (Cambridge, England) 39 28694256
2011 LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways. Bone 34 21645651
2010 Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo. PloS one 34 20383322
2018 The synaptic receptor Lrp4 promotes peripheral nerve regeneration. Nature communications 33 29921864
2011 The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation. Developmental dynamics : an official publication of the American Association of Anatomists 33 22038977
2015 Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis. PloS one 31 26284792
2019 Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo. iScience 29 31585407
2010 A variant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome. British journal of haematology 29 21121903
2018 Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis. Annals of the New York Academy of Sciences 28 29377176
2017 Anti-LRP4 autoantibodies in Chinese patients with myasthenia gravis. Muscle & nerve 28 28120340
2010 Lrp4: A novel modulator of extracellular signaling in craniofacial organogenesis. American journal of medical genetics. Part A 27 21108386
2022 The VWF/LRP4/αVβ3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells. Cardiovascular research 26 33576766
2021 Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis. Neurology 26 34233932
2017 Astrocytic Lrp4 (Low-Density Lipoprotein Receptor-Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A2AR (Adenosine A2A Receptor) Signaling. Stroke 26 29212737
2014 LRP4 induces extracellular matrix productions and facilitates chondrocyte differentiation. Biochemical and biophysical research communications 26 25091481
2013 Severe Cenani-Lenz syndrome caused by loss of LRP4 function. American journal of medical genetics. Part A 26 23636941
2023 Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex. Proceedings of the National Academy of Sciences of the United States of America 24 37252960
2021 Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development. Journal of developmental biology 24 33799485
2017 Neuronal LRP4 regulates synapse formation in the developing CNS. Development (Cambridge, England) 24 29061639
2013 Double seronegative myasthenia gravis with anti-LRP 4 antibodies. Neuromuscular disorders : NMD 23 23768983
2007 A role for LRP4 in neuronal cell viability is related to apoE-binding. Brain research 23 17889837
2018 Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development. Cellular and molecular life sciences : CMLS 22 30327840
2017 Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling. The Journal of cell biology 22 28193701
2015 Lrp4 domains differentially regulate limb/brain development and synaptic plasticity. PloS one 22 25688974
2014 Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome. American journal of medical genetics. Part A 22 24924585
2022 LRP4-IgG service line testing in seronegative myasthenia gravis and controls. Journal of neuroimmunology 21 35617719
2013 Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation. European journal of medical genetics 21 23664847
2020 CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction. EMBO reports 20 32558157
2018 Cenani-Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways. American journal of medical genetics. Part A 20 30569497
2017 Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis. Experimental neurology 20 28823823
2023 Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling. Frontiers in immunology 19 37790932
2018 LRP4 promotes proliferation, migration, and invasion in papillary thyroid cancer. Biochemical and biophysical research communications 19 29885843
2018 The role of agrin, Lrp4 and MuSK during dendritic arborization and synaptogenesis in cultured embryonic CNS neurons. Developmental biology 19 30385274
2018 Mutations in the fourth β-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers. Human mutation 18 29524275
2018 Characterization of the thymus in Lrp4 myasthenia gravis: Four cases. Autoimmunity reviews 17 30414949
2013 A common LRP4 haplotype is associated with bone mineral density and hip geometry in men-data from the Odense Androgen Study (OAS). Bone 17 23321396
2013 Mesdc2 plays a key role in cell-surface expression of Lrp4 and postsynaptic specialization in myotubes. FEBS letters 17 24140340
2022 Competitive blocking of LRP4-sclerostin binding interface strongly promotes bone anabolic functions. Cellular and molecular life sciences : CMLS 16 35099616
2018 Lrp4/Wise regulates palatal rugae development through Turing-type reaction-diffusion mechanisms. PloS one 16 30235284
2017 Immunization with Recombinantly Expressed LRP4 Induces Experimental Autoimmune Myasthenia Gravis in C57BL/6 Mice. Immunological investigations 16 28375749
2024 Functional Signature of LRP4 Antibodies in Myasthenia Gravis. Neurology(R) neuroimmunology & neuroinflammation 15 38507656
2021 Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy. Human molecular genetics 15 33987657
2021 Agrin/Lrp4 signal constrains MuSK-dependent neuromuscular synapse development in appendicular muscle. Development (Cambridge, England) 15 34714331
2008 New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation. Neuron 15 19038209
2006 Expression of low density lipoprotein receptor-related protein 4 (Lrp4) gene in the mouse germ cells. Gene expression patterns : GEP 15 16434236
2020 LRP4 promotes migration and invasion of gastric cancer under the regulation of microRNA-140-5p. Cancer biomarkers : section A of Disease markers 14 32675391
2023 The collagen ColQ binds to LRP4 and regulates the activation of the Muscle-Specific Kinase-LRP4 receptor complex by agrin at the neuromuscular junction. The Journal of biological chemistry 13 37356721
2017 The Roles of the Wnt-Antagonists Axin and Lrp4 during Embryogenesis of the Red Flour Beetle Tribolium castaneum. Journal of developmental biology 13 29615567
2023 Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals. Nature communications 12 36765071
2021 Synapse-specific Lrp4 mRNA enrichment requires Lrp4/MuSK signaling, muscle activity and Wnt non-canonical pathway. Cell & bioscience 12 34090516
2016 Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis: Defects in the pathways of amniotic fluid clearance. Scientific reports 12 26847765
2017 Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms. European journal of medical genetics 11 28559208
2020 Neuronal MT1-MMP mediates ECM clearance and Lrp4 cleavage for agrin deposition and signaling in presynaptic development. Journal of cell science 10 32591486
2019 Pathogenic effects of agrin V1727F mutation are isoform specific and decrease its expression and affinity for HSPGs and LRP4. Human molecular genetics 9 30994901
2018 Anti-AChR, MuSK, and LRP4 antibodies coexistence: A rare and distinct subtype of myasthenia gravis from Indian subcontinent. Clinica chimica acta; international journal of clinical chemistry 9 30006288

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